Alzheimer's disease (AD) is a devastating neurodegenerative disorder that ultimately leads to cognitive dysfunction and death. Largely overlooked, however, are the neuropsychiatric symptoms of AD which rob individuals of their personalities and psychological well-being and present a significant burden to care-givers. Furthermore, these symptoms occur early in disease progression and may occur years prior to AD diagnosis. The hallmark of the neuropsychiatric symptoms of AD is an inability to regulate emotional information, leading to apathy, irritability, major depression, aggression, and anxiety in a large majority of AD patients. The underlying causes of these symptoms are unknown. We hypothesize that the underlying cause of impaired emotional regulation in the AD brain is A-dependent impaired function of the neuronal circuit between the hippocampus, amygdala, and prefrontal cortex. In order to evaluate emotional processing, we will use the well-validated paradigm of fear conditioning to test the acquisition and persistence of an emotionally- charged memory in a mouse model of amyloidosis (APP/PS1 mice). We present evidence that young APP/PS1 mice (4 mo) show a pronounced deficit in extinction of emotional memory (i.e. inappropriate persistence of a fear-response in the absence of reinforcement) when compared with age-matched wild-type (WT) mice. This extinction deficit was associated with exaggerated neuronal activation in the lateral nuclei of the amygdala and an increase in soluble A in the hippocampus and amygdala. These data strongly suggest that activation of the emotion circuit by exposure to contextual fear conditioning leads to altered neuronal activation profiles that correlate with activity-dependent changes in A levels in APP/PS1 mice. The aims detailed in this proposal will expand on this preliminary data, leading to a greater understanding of how amyloid pathology contributes to neuropsychiatric symptoms of AD. Aim-1A will identify changes in neuronal network activity and A production that co-occur with behavioral changes in fear conditioning in young APP/PS1 mice. Aim-1B will use microdialysis of ISF A to measure changes in A production during the fear conditioning paradigm with high temporal resolution. Microdialysis will be combined with in vivo local field potential recordings to directly assess neural network activity. Aim-2 will determine the extent to which altering the clearance of A can rescue the neuronal and behavioral dysfunction in young APP/PS1 mice during fear conditioning. To accomplish this goal, bexarotene, a nuclear receptor agonist that increases clearance of A from the brain, will be administered. These aims represent a novel, systems level approach to examine a previously underappreciated component of AD. Determining the causes of early neuropsychiatric dysfunction in AD will lead to earlier diagnoses and more effective, preventive treatment.